Date of Award

2-2004

Degree Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Medical Sciences

Supervisor

George J.F. Heigenhauser

Abstract

The mechanisms regulating the rate-determining enzyme of carbohydrate oxidation, pyruvate dehydrogenase (PDH), were examined in human skeletal muscle at rest and during exercise in response to acute respiratory alkalosis and short- and long-term aerobic training. Voluntary hyperventilation-induced respiratory alkalosis (R-Alk) delayed PDH activation during the transition from rest to submaximal exercise. A mismatch between pyruvate production and its oxidation in R-Alk resulted in a 35% higher lactate accumulation. These effects were not seen during steady state exercise. The results from this study suggest that respiratory alkalosis may play an important role in lactate accumulation during the transition from rest to exercise in acute hypoxic conditions, but that other factors mediate lactate accumulation during steady state exercise. Short-term aerobic training did not alter resting skeletal muscle total PDH (PDHt) and PDH kinase (PDK) activities, or their respective protein expressions compared to pre-training. In contrast, long-term aerobic training (Post) compared to pre-training (Pre) resulted in a 31% increased total PDHt activity, partially due to a 1.3 fold increased protein expression of a PDH subunit, PDHE 1 α. Despite the increased PDHt activity post-training, there was an approximate 37% attenuated activation of PDH Post after 15 min of exercise at the same absolute submaximal workload compared to Pre. PDK demonstrated a 2 fold increased activity Post, partially attributed to a 1.3 fold increased PDK2 isoform protein expression. The training-induced increased PDK2 isoform expression, pyruvate-sensitive PDK isoform, coincided with an attenuated skeletal muscle pyruvate content Post during submaximal exercise at the same absolute workload. The results of these findings suggest that aerobically trained human skeletal muscle has an increased maximal capacity to utilize carbohydrates, evident by increased PDHt, but increased metabolic control sensitivity to pyruvate during submaximal exercise through increased contribution of PDK2 to total PDK activity.

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